Abstract 14048: Stromal Cell-Derived Factor-1α-Encapsulated Nanoparticles Specifically Target the Ischemic Myocardium and Attenuate Myocardial Injury via Proangiogenic Effects

Abstract

Hypothesis: Intravenously injected nanoparticles (NPs) containing stromal cell-derived factor-1α (SDF-1α) (SDF-NPs) could sustainably target the ischemia reperfusion (I/R)-injured myocardium and induce robust angiogenesis by increasing systemic EPC levels, thereby attenuating myocardial I/R injury. Methods: Male Wistar rats were subjected to myocardial I/R insult by ligating the left anterior descending artery for 30 min followed by reperfusion. At reperfusion, rats were randomized to receive intravenous injections of 5 mL/kg of phosphate-buffered saline (PBS), 6 μg/kg of NPs, SDF-1α, or SDF-NPs. One and 4 days after the treatments, SDF concentrations in the plasma and cardiac tissue, and the EPC population in the circulating blood were assessed. Therapeutic efficacy was investigated using histopathology and cardiac functional studies 4 weeks after the treatments. Results: Four days after the treatments, intravenously injected SDF-NPs circulated and accumulated selectively in the ischemic myocardium (Figure), with an SDF concentration roughly three times that of the other three treatments. SDF-NP-treated rats had more EPCs in the blood and preserved capillaries and arterioles in the ischemic border myocardium 4 weeks after treatment, which improved microvascular perfusion, reduced fibrosis, and preserved heart function. Of note, the hearts treated with SDF-NPs retained left ventricular function at 4 weeks compared to 1 day post-treatment, with an increase in the ejection fraction of 2.7±1.2%. The other three treatments decreased left ventricular function at 4 weeks (PBS: -7.8±1.2%, P<0.001; empty NPs: -3.9±1.3%, P=0.004; and SDF solution: -5.1±1.3%, P=0.001). Conclusions: Intravenous SDF-NPs selectively accumulate in ischemic cardiac tissue, protecting the myocardium from I/R injury via angiogenic effects along with EPC migration. This novel cardioprotective drug may be clinically translatable.